The mission of my Neuroimmunology Research Program is to develop a deep biological understanding of autoimmune, demyelinating and neurodegenerative processes that affect the central nervous system (CNS) and to identify and test novel disease-relevant therapies that can be brought to market to treat and/or cure these conditions. Veterans are currently developing intractable chronic neurological diseases such as multiple sclerosis (MS) and stroke, service related injuries including traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD), and substance abuse of alcohol and methamphetamine. Studies carried out by our laboratory are highly relevant to these devastating conditions due to our development of a novel therapy that targets a common underlying mechanism, the MIF/CD74 axis that promotes chronic inflammation in the CNS and other tissues. MIF (macrophage migration inhibitory factor) and its homolog D-DT (D-dopachrome tautomerase) are highly inflammatory cytokines that trigger release of other inflammatory factors upon binding and signaling through their common receptor, CD74, a chaperone for loading self and foreign peptides into MHC class II molecules on antigen presenting cells (APC). The result of MIF/CD74 signaling is peptide-specific Teffector cell activation and recruitment of inflammatory cells from blood into the CNS. Our initial unique therapeutic construct, called RTL1000 is comprised of linked DR?1 and DR?1 domains of HLA-DR2 (an MS risk factor) covalently linked to myelin oligodendrocyte glycoprotein (MOG) 35-55. This construct has conformational similarity to naturally occurring MHC class II/peptide T cell receptor ligands, but induces T cell tolerance when present in soluble form without cell-bound co-stimulatory molecules on APC. This construct has immunoregulatory and neuroprotective properties in a mouse model of MS (experimental autoimmune encephalomyelitis, EAE) and was shown to be safe and well tolerated in a Phase 1 study in MS. RTL1000 will soon be tested in a multi-dose MS clinical trial. The major breakthrough in understanding the potent effects of RTL1000 occurred in 2013 with the discovery of CD74 as the cellular receptor for RTL1000. This led to the unifying discovery that RTL1000 could competitively inhibit binding of both MIF and D-DT to CD74 and thus short-circuit MIF/CD74 signaling that is present in essentially all of the VA targeted CNS conditions. Molecular modeling of MIF binding revealed two discrete CD74 regions that bound to homologous sequences on MIF and D-DT and to the DR?1 moiety of RTL1000, thus explaining RTL1000?s competitive inhibition. However, RTL1000 can only be used in ~60% of MS subjects that express HLA-DR2. We thus designed a new construct, DR?1-MOG-35-55 that retained the activities of RTL1000 and could modulate CD74 and competitively block MIF binding, resulting in a significant treatment effect and neuroprotection in chronic EAE. Of interest, RTL1000 and DR?1-MOG-35-55 were more effective in treating chronic EAE in male mice due to an antagonist effect of estrogen receptor (ESR1) in females. An evaluation of MIF, D-DT and CD74 in a ~600 subject clinical study (to be published in PNAS) revealed that male subjects with a high expression genotype for MIF (and D-DT) had an increased risk of developing progressive MS. This unique observation raises the possibility that early treatment of males with RTL1000 or DR?1-MOG-35-55 might prevent conversion to progressive MS and potentially would be effective for treating MS subjects with progressive disease. FDA IND approval of DR?1-MOG-35-55 preclinical studies would allow treatment of all MS subjects regardless of the HLA type due to its non-polymorphic, universal expression that would be tolerated by all humans and thus could be injected without tissue typing. Of broader importance, we have demonstrated that RTL1000 and DR?1-MOG-35-55 constructs can also treat other CNS conditions in experimental mouse models including experimental stroke, vascular dementia, traumatic brain injury and methamphetamine induced cognitive disability, thus providing a novel potential therapy for Veterans that develop these devastating conditions.